TABLE 2.
Summary of in vivo studies on the neuroprotective effects of lipoxins.
| Disease type | Object | Substance | Outcome | Mechanism | References |
|---|---|---|---|---|---|
| Ischemia/reperfusion injury | Rat; mice | LXA4, LXA4 ME, ATL, BML-111 | Infarct volume, brain water content, tissue damage, hemorrhagic transformation, neurologic deficit and cognitive impairment attenuated; BBB dysfunction ameliorated; the reactivity of the cerebral microvasculature inhibited; the cognitive function improved | Anti-apoptosis; inhibition of neutrophil infiltration, lipid peroxidation, and astrocyte activation; anti-inflammation; inhibition of 5-LOX translocation and leukotriene biosynthesis; downregulation of MMP-9 and MMP-3 expression and upregulation of TIMP-1 expression; involvement of the ERK signal transduction pathway; PPARγ agonistic actions; activation of neutrophil FPR2/3 regulating leukocyte-endothelial interactions and NPA formation; activation of Nrf2/HO-1/GSH signaling | Sobrado et al. (2009), Wu et al. (2010), Ye et al. (2010), Wu et al. (2012a), Wu et al. (2013), Hawkins et al. (2014), Smith et al. (2015), Han et al. (2016), Vital et al. (2016), Hawkins et al. (2017), Wu et al. (2018) |
| Intracerebral Hemorrhage | Rat | LXA4 ME | Neuronal apoptosis and cerebral edema reduced; neurologic function improved; the levels of proinflammatory cytokines decreased | Inhibition in NF-kB-dependent MMP-9 pathway | Song et al. (2019) |
| Subarachnoid hemorrhage | Rat | LXA4 | Brain water content and BBB permeability decreased; neurological functions and spatial learning and memory abilities improved; cerebrovascular endothelial dysfunction ameliorated; microflow recovered | Anti-inflammation (FPR2/p38 MAPK pathway); suppression infiltration of neutrophils; inhibition of NF-κB via the FPR2/ERK1/2 pathway | Guo et al. (2016), Liu et al. (2019) |
| Hypoxia/ischemia neonatal brain injury | Rat | LXA4 | Cerebral edema, infarct volume, and inflammatory responses reduced; neuronal function and tissue structure recovered; motor, learning and memory functions ameliorated; the integrity of the BBB maintained | Anti-inflammation; anti-apoptosis; anti-oxidation; inhibition of IκB/NF-κB pathway | Zhu et al. (2020) |
| Traumatic brain injury | Mice | LXA4 | Cerebral edema, infarct volume and BBB breakdown reduced | Anti-inflammation; downregulation MAPK pathway with FPR2/ALX in astrocytes | Luo et al. (2013) |
| Spinal cord injury | Rabbit | LXA4 | Neurological function improved; allodynia and hyperalgesia attenuated; lesion reduced | Anti-apoptosis; anti-oxidation; upregulation of Akt/Nrf2/HO-1 signaling | Liu et al. (2015), Martini et al. (2016), Lu et al. (2018), Liu J. et al. (2020) |
| Alzheimer’s disease | Mouse | ATL, BML-111 | Cognitive impairment reduced; the expression of synaptic proteins increased; the levels of p-tau and Aβ reduced | Anti-inflammation; anti-oxidation; activation of microglia in a non-phlogistic phenotype; suppression of NF-κB activation; anti-apoptosis; modulation of CB1 receptors; inhibition of the tau kinases GSK-3β and p38 MAPK. | Wu et al. (2011), Pamplona et al. (2012), Medeiros et al. (2013), Dunn et al. (2015), Kantarci et al. (2018) |
| Multiple sclerosis | Mouse | LXA4 | Clinical signs of experimental autoimmune encephalomyelitis ameliorated | Modulation of Th1 and Th17 response and the EAE-induced spinal cord lipidom | Derada Troletti et al. (2021) |
| Chronic cerebral hypoperfusion | Rat | LXA4 ME | Cognitive impairment reduced | Activation of ERK/Nrf2 signaling pathway; regulation of endoplasmic reticulum stress and macroautophagy | Jin et al. (2014), Jia et al. (2015) |
| Neuropathic pain | Mice; rat | LXA4, ATL, LXA4 ME | Mechanical allodynia in opioid-induced hyperalgesia, peripheral nerve injury and spinal cord injury attenuated | Anti-inflammation; inhibition of microglial activation through FPR2/ALX; inhibition of JAK2/STAT3 signaling; inactivation of NF-κB, ERK and p-JNK; inhibition of μ-receptor/PI3k-Akt signaling/NALP1 inflammasome cascade; anti- autophagy by regulating the JNK1/beclin-1/PI3KC3 axis | Tanga et al. (2005), Sun et al. (2012), Li et al. (2013), Wang et al. (2014), Miao et al. (2015), Tian et al. (2015), Martini et al. (2016), Lu et al. (2018), Jin et al. (2020) |
| Plasmodium berghei- infection | Mice | LXA4 | Survival prolonged, endothelial dysfunction ameliorated | Inhibition of IL-12 production and CD8(+) IFN-γ (+) T cells; modulation of ICAM-1 and HO-1 expression | Shryock et al. (2013), Souza et al. (2015) |
| Toxoplasma gondii infection | Mice | LXA4 | Survival prolonged | Regulation of proinflammatory responses | Aliberti et al. (2002) |
| Retinal diseases | Mice | LXA4, LXB4 | The progression of retinal degeneration delayed; photoreceptors rescued | Modulation of microglial activities and anti-inflammation | Livne-Bar et al. (2017), Lu et al. (2019) |
Akt, protein kinase B, PKB; ALXR, lipoxin A4 receptor; Aβ, Amyloid-beta; BBB, blood-brain barrier; CB1, cannabinoid receptor 1; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FPR2/ALX, formyl peptide receptor 2/LXA4 receptor; GSH, glutathione; HO-1, heme oxygenase-1; IκB, inhibitor κB; JAK2, Janus kinase 2; JNK, c-Jun N-terminal kinase; LOX, lipoxygenase; LX, lipoxin; LXA4 ME, lipoxin A4 methyl ester; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NALP1, NAcht leucine-rich-repeat protein 1; NF-κB, nuclear factor kappa B; NPA, neutrophil-platelet aggregation; Nrf2, nuclear factor erythroid 2-related factor 2; PI3k, phosphoinositide-3-kinase; PPAR, peroxisome proliferator-activated receptor; SOCS, suppressors of cytokine signaling; STAT3, signal transducer and activator of transcription 3; TIMP, metallopeptidase inhibitor.